The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation

• DOI: 10.1126/scisignal.ade4335
• Publication Date: 2024-04-02T17:58:41Z
• Authors: Manuel A. Fernand...; Michael A. Pearen; Anita G. Burgess; Maria P. Ikonomop...; Diem Hoang-Le; Berit Genz; Silvia L. Saggiomo; Sujeevi S. K. Naw...; Maura Poli; Regina Reissmann; Geoffrey N. Gobert; Urban Deutsch; Britta Engelhardt; Andrew J. Brooks; Alun Jones; Paolo Arosio; Grant A. Ramm
• Keywords: Hepatic stellate cell; Proinflammatory cytokine

Serum ferritin concentrations increase during hepatic inflammation and correlate with the severity of chronic liver disease. Here, we report a molecular mechanism whereby heavy subunit (FTH) contributes to inflammation. We found that FTH induced activation NLRP3 inflammasome secretion proinflammatory cytokine interleukin-1β (IL-1β) in primary rat stellate cells (HSCs) through intercellular adhesion molecule–1 (ICAM-1). FTH–ICAM-1 stimulated expression Il1b , activation, processing IL-1β manner depended on plasma membrane remodeling, clathrin-mediated endocytosis, lysosomal destabilization. signaling at early endosomes expression, implying this endosomal primed HSCs. In contrast, destabilization was required for FTH-induced secretion, suggesting damage activated inflammasomes. production slices from wild-type mice but not those Icam1 −/− or Nlrp3 mice. Thus, signals its receptor ICAM-1 HSCs activate inflammasome. speculate pathway inflammation, key process stimulates fibrogenesis associated